Chimeric antigen receptor T (CAR-T) cells expanded with IL-7/IL-15 mediate superior antitumor effects.
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ABSTRACT:
SUBMITTER: Zhou J
PROVIDER: S-EPMC6776495 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chimeric antigen receptor-modified (CAR-modified) T cells have shown promising therapeutic effects for hematological malignancies, yet limited and inconsistent efficacy against solid tumors. The refinement of CAR therapy requires an understanding of the optimal characteristics of the cellular products, including the appropriate composition of CD4+ and CD8+ subsets. Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor ?2 (IL13R?2). Upon stimulation with IL13R?2+ GBM cells, the CD8+ CAR T cells exhibited robust short-term effector function but became rapidly exhausted. By comparison, the CD4+ CAR T cells persisted after tumor challenge and sustained their effector potency. Mixing with CD4+ CAR T cells failed to ameliorate the effector dysfunction of CD8+ CAR T cells, while surprisingly, CD4+ CAR T cell effector potency was impaired when coapplied with CD8+ T cells. In orthotopic GBM models, CD4+ outperformed CD8+ CAR T cells, especially for long-term antitumor response. Further, maintenance of the CD4+ subset was positively correlated with the recursive killing ability of CAR T cell products derived from GBM patients. These findings identify CD4+ CAR T cells as a highly potent and clinically important T cell subset for effective CAR therapy.
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Project description:Chimeric antigen receptors (CAR) are genetically engineered receptors that can recognise specific antigens and subsequently activate downstream signalling. Human T cells engineered to express a CAR, also known as CAR-T cells, can target a specific tumour antigen on the cell surface to mediate a cytotoxic response against the tumour. CAR-T cell therapy has achieved remarkable success in treating hematologic malignancies, but not in solid tumours. Currently, extensive research is being carried out to make CAR-T cells a therapy for solid tumours. To date, most of the research interest in the field has focused on cytotoxic T lymphocytes as the carrier of CAR products. However, in addition to T cells, the CAR design can be introduced in other immune cells, such as natural killer (NK)/NKT cells, γδ T cells, mucosal-associated invariant T (MAIT) cells, dendritic cells (DC), macrophages, regulatory T cells (Treg), B cells, etc. Some of the CAR-engineered immune cells, such as CAR- γδ T and CAR-NK/NK-T cells, are directly involved in the anti-tumour response, demonstrated in preclinical studies and/or clinical trials. CAR-Tregs showed promising therapeutic potential in treating autoimmune diseases. In particular, B cells engineered with chimeric receptors can be used as a platform for long-term delivery of therapeutic proteins, such as recombinant antibodies or protein replacement, in an antigen-specific manner. CAR technology is one of the most powerful engineering platforms in immunotherapy, especially for the treatment of cancers. In this review, we will discuss the recent application of the CAR design in non-CAR-T cells and future opportunities in immunotherapy.
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Project description:The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor ?-chain (IL-2R?) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-?IL2RB-z(YXXQ)). The 28-?IL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-?IL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken together, these results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted.
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Project description:Despite remarkable progress in B cell malignancies, T cells expressing chimeric antigen receptors (CARs) remain ineffective in solid tumors in part because T cells do not traffic effectively to or survive in tumor tissues. We engineered Vα24-invariant natural killer T cells (NKTs), which intrinsically home to tumor sites, to co-express a GD2-specific CAR with interleukin (IL)15 and evaluated their therapeutic efficacy in children with relapsed/resistant neuroblastoma (NB)(NCT03294954). The first three patients received a single infusion of 3x10e6 autologous CAR-NKTs per square meter of body surface area and tolerated the treatment well. CAR-NKTs expanded in vivo, localized to the tumor, and in one patient induced a near-complete regression of bone metastatic lesions.
2020-08-10 | GSE154037 | GEO
Project description:Human T cells isolated from healthy donors were transduced with non-tonically signaling CARs or tonically signaling CARs, each with CD28z or 4-1BB costimulatory domains Human T cells isolated from healthy donors were transduced with non-tonically signaling CARs or tonically signaling CARs, each with CD28z or 4-1BB costimulatory domains
2015-04-09 | E-GEOD-65856 | biostudies-arrayexpress
Project description:Chimeric antigen receptors (CARs) usually combine the antigen binding site of a monoclonal antibody with the signal activating machinery of a T cell, freeing antigen recognition from MHC restriction and thus breaking one of the barriers to more widespread application of cellular therapy. Similar to treatment strategies employing monoclonal antibodies, T cells expressing CARs are highly targeted, but additionally offer the potential benefits of active trafficking to tumor sites, in vivo expansion and long-term persistence. Furthermore, gene transfer allows the introduction of countermeasures to tumor immune evasion and of safety mechanisms.The basic structure of so-called first and later generation CARs and their potential advantages over other immune therapy systems. How these molecules can be grafted into immune cells (including retroviral and non-retroviral transduction methods) and strategies to improve the in vivo persistence and function of immune cells expressing CARs. Examples of tumor-associated antigens that have been targeted in preclinical models and clinical experience with these modified cells. Safety issues surrounding CAR gene transfer into T cells and potential solutions to them.Because of recent advances in immunology, genetics and cell processing, CAR-modified T cells will likely play an increasing role in the cellular therapy of cancer, chronic infections and autoimmune disorders.
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Project description:Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor's individual components-scFv, spacer domain, and costimulatory domains-and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.
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Project description:Chimeric antigen receptor (CAR) T cells are patient T cells that are transduced with genetically engineered synthetic receptors to target a cancer cell surface antigen. The remarkable clinical response rates achieved by adoptive transfer of T cells that target CD19 in patients with leukemia and lymphoma have led to a growing number of clinical trials exploring CAR T-cell therapy for solid tumors. Herein, we review the evolution of adoptive T-cell therapy; highlight advances in CAR T-cell therapy for thoracic malignancies; and summarize the targets being investigated in clinical trials for patients with lung cancer, malignant pleural mesothelioma, and esophageal cancer. We further discuss the barriers to successfully translating CAR T-cell therapy for solid tumors and present strategies that have been investigated to overcome these hurdles.
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Project description:Adoptive T-cell therapy with gene-modified T cells expressing a tumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a rapidly growing field of translational medicine and has shown success in the treatment of B-cell malignancies and solid tumors. In all reported trials, patients have received T-cell products comprising random compositions of CD4(+) and CD8(+) naive and memory T cells, meaning that each patient received a different therapeutic agent. This variation may have influenced the efficacy of T-cell therapy, and complicates comparison of outcomes between different patients and across trials. We analyzed CD19 CAR-expressing effector T cells derived from different subsets (CD4(+)/CD8(+) naive, central memory, effector memory). T cells derived from each of the subsets were efficiently transduced and expanded, but showed clear differences in effector function and proliferation in vitro and in vivo. Combining the most potent CD4(+) and CD8(+) CAR-expressing subsets, resulted in synergistic antitumor effects in vivo. We show that CAR-T-cell products generated from defined T-cell subsets can provide uniform potency compared with products derived from unselected T cells that vary in phenotypic composition. These findings have important implications for the formulation of T-cell products for adoptive therapies.
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Project description:Natural killer (NK) cells are potential effector cells in cell-based cancer immunotherapy, particularly in the control of hematological malignancies. The chimeric antigen receptor (CAR) is an artificially modified fusion protein that consists of an extracellular antigen recognition domain fused to an intracellular signaling domain. T cells genetically modified with a CAR have demonstrated remarkable success in the treatment of hematological cancers. Compared to T cells, CAR-transduced NK cells (CAR-NK) exhibit several advantages, such as safety in clinical use, the mechanisms by which they recognize cancer cells, and their abundance in clinical samples. Human primary NK cells and the NK-92 cell line have been successfully transduced to express CARs against both hematological cancers and solid tumors in pre-clinical and clinical trials. However, many challenges and obstacles remain, such as the ex vivo expansion of CAR-modified primary NK cells and the low transduction efficiency of NK cells. Many strategies and technologies have been developed to improve the safety and therapeutic efficacy in CAR-based immunotherapy. Moreover, NK cells express a variety of activating receptors (NKRs), such as CD16, NKG2D, CD226 and NKp30, which might specifically recognize the ligands expressed on tumor cells. Based on the principle of NKR recognition, a strategy that targets NKRs is rapidly emerging. Given the promising clinical progress described in this review, CAR- and NKR-NK cell-based immunotherapy are likely promising new strategies for cancer therapy.
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